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The tumour suppressor C/EBP delta inhibits FBXW7 expression and promotes mammary tumour metastasis

  1. Author:
    Balamurugan, K.
    Wang, J. M.
    Tsai, H. H.
    Sharan, S.
    Anver, M.
    Leighty, R.
    Sterneck, E.

  2. Author Address

    [Balamurugan, Kuppusamy; Sharan, Shikha; Sterneck, Esta] NCI, Lab Cell & Dev Signalling, CCR, Frederick, MD 21702 USA. [Wang, Ju-Ming; Tsai, Hsin-Hwa] Natl Cheng Kung Univ, Coll Biosci & Biotechnol, Inst Bioinformat & Biosignal Transduct, Tainan 70101, Taiwan. [Anver, Miriam] NCI, Pathol Histotechnol Lab, SAIC Frederick, Frederick, MD 21702 USA. [Leighty, Robert] NCI, Data Management Serv Inc, Frederick, MD 21702 USA.;Sterneck, E, NCI, Lab Cell & Dev Signalling, CCR, 1050 Boyles St,Bldg 560, Frederick, MD 21702 USA.;sternecg@mail.nih.gov
    1. Year: 2010
    2. Date: Dec
  2. Journal: Embo Journal
    1. 29
    2. 24
    3. Pages: 4106-4117
  4. Type of Article: Article
  5. ISSN: 0261-4189
  1. Abstract:

    Inflammation and hypoxia are known to promote the metastatic progression of tumours. The CCAAT/enhancer-binding protein-delta (C/EBP delta, CEBPD) is an inflammatory response gene and candidate tumour suppressor, but its physiological role in tumourigenesis in vivo is unknown. Here, we demonstrate a tumour suppressor function of C/EBP delta using transgenic mice overexpressing the Neu/Her2/ERBB2 proto-oncogene in the mammary gland. Unexpectedly, this study also revealed that C/EBP delta is necessary for efficient tumour metastasis. We show that C/EBP delta is induced by hypoxia in tumours in vivo and in breast tumour cells in vitro, and that C/EBP delta-deficient cells exhibit reduced glycolytic metabolism and cell viability under hypoxia. C/EBP delta supports CXCR4 expression. On the other hand, C/EBP delta directly inhibits expression of the tumour suppressor F-box and WD repeat-domain containing 7 gene (FBXW7, FBW7, AGO, Cdc4), encoding an F-box protein that promotes degradation of the mammalian target of rapamycin (mTOR). Consequently, C/EBP delta enhances mTOR/AKT/S6K1 signalling and augments translation and activity of hypoxia-inducible factor-1 alpha (HIF-1 alpha), which is necessary for hypoxia adaptation. This work provides new insight into the mechanisms by which metastasis-promoting signals are induced specifically under hypoxia. The EMBO Journal (2010) 29, 4106-4117. doi: 10.1038/emboj.2010.280; Published online 12 November 2010

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External Sources

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  2. DOI: 10.1038/emboj.2010.280
  3. View record in Web of Science®
  4. WOS: 000285407200007

Library Notes

  1. Fiscal Year: FY2010-2011
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